Ophthalmic composition comprising a beta -blocker

ABSTRACT

The invention concerns an ophthalmic composition comprising a beta-blocker solution, said composition being obtained by dissolving in water beta-blocker in the presence of alginic acid and adding an alkaline base, to obtain a solution with the PH of 6 to 8. Said composition has a sustained duration of action.

The present invention relates to ophthalmic compositions comprising aβ-blocker.

Ophthalmic compositions comprising β-blockers are used in the treatmentof ocular hypertension and of glaucoma. As examples, there may bementioned collyria based on carteolol, timolol, befunolol, metipranolol,levobunolol, pindolol or betaxolol. These solutions have a relativelyshort duration of action, such that the administration of these collyriashould be repeated during the day.

Cohen et al. (Journal of Control Release, 44, 201, 1997) have moreoverproposed aqueous solutions of pilocarpine containing a sodium alginatewith a high guluronic acid content, which form a gel when the solutionis applied to the eye (apparently because of the action of the calciumions present in the lachrymal fluid) and make it possible to obtain aprolonged duration of action.

The inventors have however observed that if this system is applied toβ-blockers, that is to say if a β-blocker is added to a sodium alginatesolution, no prolonged effect is obtained after administration of thesolution.

The inventors have on the other hand discovered that if a β-blocker isadded to an aqueous composition containing alginic acid and the pH isincreased by addition of an alkaline base, a solution is obtained whichmakes it possible to obtain a prolonged effect after administration andwhich thereby allows a single daily administration.

The subject of the present invention is thus an ophthalmic compositioncomprising a β-blocker in solution, this composition being obtained bydissolving the β-blocker in water in the presence of alginic acid andadding an alkaline base, in order to obtain a solution having a pH of 6to 8.

The subject of the present invention is also a method of preparing anophthalmic composition, consisting in dissolving a β-blocker in water inthe presence of alginic acid and in adding an alkaline base in order tobring its pH to a value of 6 to 8.

The alginic acid is preferably an alginic acid having a guluronic acidcontent of at least 40% and, preferably, of at least 65%, for example analginic acid having a guluronic acid content of 65 to 75%.

The β-blockers present in the composition may be chosen in particularfrom carteolol, timolol, befunolol, metipranolol, levobunolol, pindololor betaxolol.

The β-blockers are added in general in the form of salts withpharmaceutically acceptable acids.

They are generally present at concentrations of 0.01 to 5% andpreferably of 0.1 to 2% (expressed in the form of a base) of the weightof the final composition.

The alginic acid is used at concentrations of 0.01 to 5% and,preferably, between 0.1 and 2% of the weight of the final composition.

The alginic acid/β-blocker (expressed in the form of a base) weightratio is in general from 0.1 to 20 and preferably from 0.2 to 10.

The alkaline base is an alkali metal hydroxide or a basic salt of analkali metal and is preferably sodium hydroxide.

The composition may in addition contain a buffer mixture such as aphosphate buffer, an isotonizing agent such as sodium chloride,stabilizers such as an antioxidant and/or a chelating agent (for exampleEDTA), as well as a preservative such as benzalkonium chloride.

Results of trials demonstrating the effects obtained with thecompositions according to the invention will be given below.

1) COMPARATIVE TRIALS WITH CARTEOLOL

The procedures used were the following:

Procedure 1

Alginic acid is suspended in about 50 ml of purified water and carteololhydrochloride (2 g) is dissolved therein. The pH is then close to 3.

The phosphate buffer (0.1 g of sodium hydrogen phosphate dodecahydrateand 0.04 g of sodium dihydrogen phosphate dihydrate) is added followedby sodium chloride. The pH then reaches a value close to 3.5.

The pH is adjusted to 6.8 with a 1 N sodium hydroxide solution andbenzalkonium chloride (0.005 g) is incorporated therein.

The volume is finally adjusted to 100 ml by addition of purified water.

Procedure 2

Sodium alginate is dissolved in about 50 ml of purified water, the valueof the pH is close to 8.

Carteolol hydrochloride (2 g), phosphate buffer and sodium chloride aredissolved in 40 ml of purified water (the pH of the solution is close to6.8).

This solution is added to the aqueous solution of sodium alginate andthe pH adjusted to 6.8 by addition of dilute hydrochloric acid.

Benzalkonium chloride (0.005 g) is incorporated therein and the finalvolume is adjusted to 100 ml by addition of purified water.

Procedure 3

Alginic acid is suspended in about 50 ml of purified water and then thepH is adjusted to 8 by addition of a 1 N sodium hydroxide solution.

Carteolol hydrochloride (2 g), phosphate buffer and sodium chloride aredissolved in 40 ml of purified water (the pH of the solution is close to6.8).

This latter solution is added to the neutralized alginic acid solutionand the pH is adjusted to 6.8 by addition of dilute hydrochloric acid.

Benzalkonium chloride (0.005 g) is incorporated therein and the finalvolume is adjusted to 100 ml by addition of purified water.

These compositions were tested in a model of ocular hypertensiontriggered in rabbits.

Animals

The experiments were performed on New Zealand male albino rabbitsobtained from the Charles River Breeding Farm, France (St Aubin lesElbeuf, 76140 Cléon) acclimatized for a minimum of five days in theanimal house (temperature: 19±2° C., relative humidity: 55±10%,illumination: 12 hours of daylight—12 hours of darkness).

Ocular Hypertension Triggered by Aqueous Fluid Overload

The animals were starved of food on the day before the experiments. Onthe day of the experiment, the animals were conditioned to stalling in arestraining cage and to the measurement of intraocular pressure (IOP)until a stable base value is obtained. The IOP was measured with the aidof an ALCON aplanation pneumatonograph or a MENTOR® pneumatonometer(model 30 Classic), without preliminary local anaesthesia.

The ophthalmic preparations tested were then administered in one eye, ina volume of 25 μl, at various times before the aqueous fluid overload:the contralateral eye received no treatment and served as a control.

The experimental ocular hypertension was induced in the two eyes by oraladministration of water at 37° C. (70 ml/kg in less than 30 seconds; 200ml for the rabbits having a weight greater than 3 kg). The IOP wasmeasured in the two eyes before, and then every ten minutes for one hourafter the aqueous fluid overload.

The ocular hypotensive activity of the preparations tested is calculatedfrom the increases in IOP in the treated eye and the control eye, at theexperimental hypertension peak; it is expressed as a percentage ofinhibition of the hypertension (mean±standard deviation).

Estimation of the Maximum Activity and of the Duration of Action of thePreparations Tested

The ocular hypertension triggered by an aqueous fluid overload is anacute hypertension since the IOP returns to its base value on averageone hour after the aqueous fluid overload. The hypotensive activity peakand the duration of action of the preparations tested cannot thereforebe evaluated in a single experiment; a fairly precise estimation ofthese two parameters is obtained indirectly on several experiments byvarying the time of administration of the preparations in relation tothe aqueous fluid overload (pretreatment time).

The results are assembled in the table below.

TABLE Ocular hypotensive activity expressed as % inhibition of thehypertension induced by an aqueous fluid overload in rabbits Com- posi-Pretreatment time tion Alginic derivative 1 h 6 h 8 h 1 — 25.5 ± 6.215.2 ± 8.2 0.6 ± 5.6 (13) ** (8) (4) 2 (1) * Alginic acid 1% 24.4 ± 4.813.2 ± 6.0 10.0 ± 6.1  (G = between 65 (5) (5) (4) and 75%) 3 (1)Alginic acid 1% 12.5 ± 2.1 3.6 ± 4.0 (G = 39%) (4) (5) 4 (2) Sodiumalginate 1.9 ± 1.5 1% LVG (4) (G = between 65 and 75%) 5 (2) Sodiumalginate −0.2 ± 1.6   1% MVG (4) (G = between 65 and 75%) 6 (3) Sodiumalginate formed 1.6 ± 3.5 in situ from alginic (5) acid 1% (G = between65 and 75%) * ( ) procedure ** ( ) number of animals G: guluronic acidcontent LVG: low viscosity; MVG = medium viscosity.

An ophthalmic solution based on 2% carteolol hydrochloride with noalginic derivative (composition 1) no longer has any activity after 8h00of pretreatment.

A corresponding ophthalmic composition according to the invention(composition 2) containing 1% alginic acid (alginic acid containingbetween 65 and 75% of guluronic acid) still has at time 8h00 asignificant inhibition of the ocular hypertension.

The use of alginic acid at the concentration of 1% whose guluronic acidcontent is 39% leads to a carteolol hydrochloride composition at 2%(composition 3) inducing a lower reduction in the ocular hypertension attime 8h00 than a composition containing 1% of alginic acid whoseguluronic acid content is higher, between 65 and 75%.

The use of sodium alginate at the concentration of 1% whose guluronicacid content is between 65 and 75% does not make it possible to obtainophthalmic compositions based on 2% carteolol hydrochloride exhibitinginhibition of the ocular hypertension after 8h00 of pretreatment. Theseresults are observed with sodium alginate of low viscosity and of mediumviscosity (compositions 4 and 5).

If, during the preparation of the ophthalmic composition, the alginicacid (at the concentration of 1%) is salified by addition of sodiumhydroxide to pH 8 before the addition of carteolol hydrochloride, noinhibition of the ocular hypertension induced is observed after 8h00 ofpretreatment (composition 6). The formation of alginate in situ fromalginic acid with a guluronic acid content of between 65 and 75% doesnot make it possible to obtain the pharmacological effect observed withcomposition 2.

2) Trials with β-blockers Other than Carteolol

a) Timolol

A study of the ocular hypotensive activity as a function of the alginicacid concentration (% expressed by weight relative to the weight of thefinal composition) was carried out on timolol at the concentration of0.5% (expressed as a base; that is 0.683% of timolol maleate) inpreparations according to procedure 1 using an alginic acid with a highguluronic acid content (G greater than 65%):

Ocular Hypotensive Activity Expressed as % Inhibition of theHypertension Induced by an Aqueous Fluid Overload in Rabbits

Alginic acid (as % of the weight of the final Pretreatment timecomposition) 6 h 8 h 0*   13.2 ± 4.3 (4) 1.5 ± 4.4 (6) 0.16 8.5 ± 2.7(4) 0.32 7.6 ± 4.2 (4) 0.64 8.2 ± 4.0 (5) *commercial collyriumcontaining 0.5% of timolol expressed as a base.

The commercial reference collyrium no longer has any activity after 8h00of pretreatment. On the other hand, the effect is prolonged when thecomposition contains alginic acid.

b) Pindolol

A similar study was carried out with pindolol, used in the form of abase, at the concentration of 1%.

Alginic acid (as % of the weight of the final Pretreatment timecomposition) 1 h 4 h 0*  13.0 ± 6.6 (4) −3.0 ± 8.7 (7)   0.8 10.3 ± 4.4(4)   1.6   6.8 ± 1.7 (4)  *commercial collyrium containing 1% ofpindolol.

The commercial collyrium no longer has any activity after 4h00 ofpretreatment.

The addition of alginic acid makes it possible to increase the durationof action of 1% pindolol.

3) Additional Trials on Carteolol

The ocular hypotensive activity of carteolol as a function of thealginic acid concentration was studied for various concentrations ofcarteolol hydrochloride: 0.5%-1% and 2% (that is respectively0.44%-0.89% and 1.78% expressed in the form of a base).

The results are given in the following three tables, in comparison withcommercial collyria without alginic acid and containing 0.5%-1% and 2%of carteolol hydrochloride.

0.5% carteolol hydrochloride

Alginic acid (as % of the weight of the final Pretreatment timecomposition) 4 h 6 h 0 11.4 ± 4.3 (4) 1.3 ± 1.7 (4) 0.25 8.8 ± 4.7 (5) 15.9 ± 3.1 (5)

1% carteolol hydrochloride

Alginic acid (as % of the weight of the final Pretreatment timecomposition) 6 h 6 h 0 10.6 ± 3.9 (4)  −0.2 ± 2.8 (5)   0.5  6.3 ± 2.8(4) 1 10.1 ± 3.8 (4)

2% carteolol hydrochloride

Alginic acid (as % of the weight of the final Pretreatment timecomposition) 6 h 8 h 0 15.2 ± 8.2 (8)  0.6 ± 5.6 (4) 1  8.0 ± 2.7 (4) 211.4 ± 2.2 (5)

What is claimed is:
 1. Ophthalmic composition comprising a β-blocker insolution, this composition being obtained by dissolving the β-blocker inan aqueous alginic acid solution and then adding an alkaline base, inorder to obtain a solution having a pH of 6 to
 8. 2. Compositionaccording to claim 1, in which the alginic acid has a guluronic acidcontent of at least 40%.
 3. Composition according to claim 2, in whichthe alginic acid has a guluronic acid content of at least 65%. 4.Composition according to claim 1, in which the β-blocker is chosen fromcarteolol, timolol and pindolol.
 5. Composition according to claim 1, inwhich the β-blocker is present at a concentration of 0.01 to 5% byweight.
 6. Composition according to claim 1, in which the alginic acidis present at a concentration of 0.01 to 5% by weight.
 7. Compositionaccording to claim 1, in which the alginic acid/β-blocker weight ratiois from 0.1 to
 20. 8. Composition according to claim 7, in which thealginic acid/β-blocker weight ratio is from 0.2 to
 10. 9. Method ofpreparing an ophthalmic composition, comprising dissolving a β-blockerin an aqueous alginic acid solution and then adding an alkaline base inorder to bring its pH to a value of 6 to 8.